EP1756110A1 - 7H-PYRROLO[2,3-d]PYRIMIDINDERIVATE SOWIE DEREN THERAPEUTISCH ANNEHMBARE SALZE, PHARMAZEUTISCHE ZUBEREITUNGEN, DIE DIESE ENTHALTEN, UND VERFAHREN ZUR HERSTELLUNG DES WIRKSTOFFS - Google Patents

7H-PYRROLO[2,3-d]PYRIMIDINDERIVATE SOWIE DEREN THERAPEUTISCH ANNEHMBARE SALZE, PHARMAZEUTISCHE ZUBEREITUNGEN, DIE DIESE ENTHALTEN, UND VERFAHREN ZUR HERSTELLUNG DES WIRKSTOFFS

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Publication number
EP1756110A1
EP1756110A1 EP05739554A EP05739554A EP1756110A1 EP 1756110 A1 EP1756110 A1 EP 1756110A1 EP 05739554 A EP05739554 A EP 05739554A EP 05739554 A EP05739554 A EP 05739554A EP 1756110 A1 EP1756110 A1 EP 1756110A1
Authority
EP
European Patent Office
Prior art keywords
general formula
alkyl
reaction
pyrrolo
methine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05739554A
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English (en)
French (fr)
Other versions
EP1756110B1 (de
Inventor
Janos Szolcsanyi
Laszlo Orfi
György KERI
Frigyes Waczek
Erika Pinter
Zsuzsanna Helyes
Tamas Szüts
József NÉMETH
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Individual
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to new 7H-pyrrolo[2,3-d]py ⁇ imidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for producing the active agent.
  • the compounds of general formula (I) are basic substances of pharmaceutical preparations of neurogenic and not neurogenic antiphlogistic, as well as paregoric effect, neuropathic hyperalgesia reducing ones, those for hindering rheumatic arthritis or treatment of destruction of bone or chondrus in joints, as well as for other diseases, which may be connected with other inflammatory processes e. g. asthma, eczema, psoriasis.
  • the invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives of the general formula (I), and to their therapeutically acceptable salts.
  • RI is alkyl, aryl, heteroaryl or aryl-alkyl with 1-4 carbon atoms group, heteroaryl- alkyl with 1-4 carbon atoms group, morpholino-alkyl with 1-4 carbon atoms group or dialkylamino-alkyl with 1-4 carbon atoms group.
  • R2, R3 independently of each other are hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl groups or R2 and R3 together are tetramethylene group.
  • R5 is substituted or unsubstituted aromatic or heteroaromatic ring
  • R6, R7, R8 and R9 are independently hydrogen, halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, methoxy, ethoxy, isopropoxy or sulfonyl group,
  • RIO is hydrogen or nitrile group
  • Rl l is hydrogen, methyl, ethyl, propyl, isopropyl, tert.- butyl group or tetramethylene ring connected to X
  • R12 is alkyl, aryl, heteroaryl, aryl-alkyl with 1-4 carbon atoms, heteroaryl-alkyl with 1-4 carbon atoms, morpholino-alkyl with 1-4 carbon atoms or dia-U lamino-alkil with 1-4 carbon atoms group,
  • X is carbon if RI 1 is a tetramethylene ring connected to X, otherwise nitrogen, methine, methyl-methine emyl-methine, propyl-methine, isopropyl-methine, cyclopropyil-methine, tert.- butyl-methine or phenyl-methine group.
  • the therapeutically acceptable salts are advantageously acid-additive ones.
  • the most characteristic compounds of the general formula (I) may be defined by general formula (la), (lb) and (Ic) where RI, R2, R3, R5, R6, R7, R8, R9, RIO, RI 1, R12 and X are the same as mentioned above.
  • the invention relates also to a pharmaceutical preparation containing the compound of general formula (I) as active substance and therapeutically acceptable additives.
  • the pharmaceutical preparation is advantageously antiphlogistic and analgetic one, a preparation reducing neuropathic hyperalgesia and rheumatic arthritis, a preparation for hindering destruction of bones or chondrus, being applicable for treatment of other diseases, which may be connected with other inflaimnatory processes e. g. asthma, eczema or psoriasis.
  • the invention relates furthermore to a process for producing 7H-pyrrolo[2,3- d]pyrimidine derivatives of the general formula (I).
  • the process may be characterized in that a compound of general formula (II) is produced from acetoine with amine and malononitrile of molar equivalent quantities where RI, R2 and R3 are the same as mentioned above.
  • reaction product is separated.
  • the compound of general formula (II) is produced in such a way that acetoine is brought into reaction with amine and malonic acid dinitrile of molar equivalent quantities.
  • the compounds of general formula (II) are produced in this way.
  • the reaction can be carried out in two stages in the same reaction mixture using either acidic or alkaline catalyst.
  • the acetoine is brought into reaction with the suitable amine always with acidic catalyst (concentrated HC1 or toluene sulphonic acid) in aprotic solvent (advantageously in toluene or benzene) at reflux temperature using water separating additive until the whole water produced in the reaction is removed then malononitrile is added and the mixture is kept at reflux temperature until removal of water of equivalent quantity.
  • acidic catalyst concentrated HC1 or toluene sulphonic acid
  • aprotic solvent advantageousously in toluene or benzene
  • amines of aniline type are used the solvent is changed to a protic one advantageously methanol, ethanol or isopropanol and they are brought into reaction with malonic acid dinitrile using alkaline medium (aqueous solution of KOH or NaOH) in inert atmosphere.
  • alkaline medium aqueous solution of KOH or NaOH
  • the intermediate compound of general formula (II) is filtered having cooled the mixture then mixed with formic acid of 5 to 10 mass excess (of 85 to 98 mass %) at reflux temperature for 1 hour to 2 days.
  • the mixture is then poured onto icy water and the precipitated product is isolated either by filtering or extraction with ethyl acetate at neutral pH.
  • the product is thoroughly dried in both cases then brought into reaction with phosphorus oxychloride of 5 to 10 times of mass excess at reflux temperature for 0.5 to 4 hours.
  • the mixture containing phosphorus oxychloride is poured onto ice and having set pH to neutral the precipitated imidoyl chloride of general formula (III) is either filtered or extracted with ethyl acetate, then the combined organic phase is dried and evaporated.
  • the imidoyl chloride of general formula (III) obtained after filtering or extracting and evaporation is solved in an aprotic solvent (THF, dioxane, DMSO or DMF) or in the mixture of them.
  • the imidoyl chloride of the general formula (III) is brought into reaction with amine of general structure (II) or (IV) of equivalent quantity adding NaH of molar equivalent excess of 2 to 10 times for 0.5 to 6 hours.
  • the reaction mixture is poured onto ice-water and processed, the precipitated product is filtered and the compounds of general formula (la) are produced by crystallizing from dioxane ethylacetate hexane mixture.
  • the imidoyl chloride of the general formula (III) produced in the above described way is brought into reaction with hydrazine hydrate of molar equivalent excess of 2 to 10 in a polar organic solvent (advantageously in methanol, ethanol, isopropanol, DMF, DMSO or in a mixture of any proportion of these solvents) then the solvent is removed under reduced pressure and thereafter the product received in this way is separated between ethyl acetate and water.
  • the organic phase is evaporated after drying and the hydrazine derivative is received by treating the residue with an apolar solvent (advantageously with hexane or ether), which is brought into reaction with aldehydes in a polar organic solvent (advantageously in methanol, ethanol, isopropanol, DMF, DMSO solvent or in glacial acetic acid) at a temperature of 20 to 100 C° for 1 to 12 hours. If the solvent is adequately chosen the product precipitates and may be separated by filtering after cooling of the mixture.
  • an apolar solvent advantageousously with hexane or ether
  • a polar organic solvent as advantageously in methanol, ethanol, isopropanol, DMF, DMSO solvent or in glacial acetic acid
  • the compounds of the general formula (lb) are obtained after a washing with an apolar solvent (advantageously with ether or hexane).
  • the version C) of the process is performed similarly but the hydrazine derivative is brought into reaction with isatin.
  • the intermediate compounds used in the process according to the invention are partly known as intermediate products of the above mentioned kinase inhibitor compounds, such as im2_l to im3_3, im3_5 and im4_l to 4, they are partly new such as the compounds given in the examples 3, 5, 6, and 8 to 11 (see Table 1).
  • the essence of the invention is based also on the recognition that new structures may be created by linking together the reactive intermediate products of known biologically active compounds using the process described in the Example 4 and compounds of new structures are obtained having astonishingly different effects from those of the known compounds.
  • the compounds according to the invention are analgesic and antiphlogistic ones, which may be potentially orally administered.
  • TT-232 is a potent analgesic hindering both the neurogenic and non-neurogenic inflammation, which is effective also in the neuropathic nociceptive model.
  • TT-232 is a peptide structure and cannot be orally absorbed
  • the in vitro tests were performed with electric excitation of senspric neuron elements of an isolated rat trachea.
  • the mediator of neurogenic inflammation the P-substance is released under influence of excitation from the capsaicine sensitive neuron elements and the concentration of P-substance in the water bath may be measured by radio immunoassay.
  • Somatostatine antagonists, as well as the TT-232 hinder the excitation of tej-minal nerves so the quantity of released neuropeptide becomes less in the water bath.
  • TT-232 The antiphlogistic efficiency of TT-232 against neurogenic and non-neurogenic inflammations was formerly tested primarily on rats (such as plasm extravasation provoked by mustard-oil, dextrane oedema, chronic arthritic oedema provoked by Freund adjuvant, plasm extravasation in articulations provoked by bradyquinine, carrageenine oedema, accumulation of leucocytes under influence of carrageenine).
  • the oedema was provoked by alcoholic solution of capsaicine onto the mouse ear in the biological tests mentioned in the patent specification, and it was quantitatively evaluated by measurement of the mass of the ear and that of Evans's blue accumulation.
  • Freund's adjuvant was demonstrated formerly on Wistar's female rat. This is the experimental model of rheumatoid arthritis. The phase II clinical trials of TT-232 on patients suffering from rheumatoid arthritis was performed in 2004. Wee took into consideration that the Freund's adjuvant aggravates symptoms implying considerable deformation of articulations on rats of Lewis strain, so the effect of
  • the NMR photos were taken by apparatus Bruker AC300.
  • the apparatus used for measurement of HPLC was:
  • the melting points were measured by the apparatus B ⁇ chi Melting Point B-540.
  • Example 1 The compounds according to the invention, the process for producing them and experiments to deteimine their effects are presented in the examples below.
  • Example 1 The compounds according to the invention, the process for producing them and experiments to deteimine their effects are presented in the examples below.
  • Example 2 40 g of 2-amino-4,5-dimemyl-l-(3-cUorophenyl)--mino-3-cyano-pyrrole (Example 1) was refluxed in 200 g of formic acid for 10 hours. The mixture was then poured onto ice and stirred for 1 hour. The precipitated material was filtered out and washed with water. The product was dried at room temperature and used in the following reaction without further purification. (27 g; 60 %).
  • Example 2 -d]py ⁇ imidine (Example 2) was solved in 125 ml of POCI3 and the mixture was
  • the compound was produced as described in the Example 5 with the difference that the primary substance was the known intermediate product marked as im3_l (2.71 g of the substance).
  • the influence of active substances on the SP release was examined in in vitro environment on rat trachea in biological bath (Wistar's rats of 200 to 250 g weight were used). Samples were taken three times in periods of 8 minutes after perfusion with oxygenated Krebs's solution for 1 hour. The organ was excited with electric current of 10 Hz, 40 V, 0.1 ms, 120 s in the middle period of 8 minutes. The SP content of the samples were measured by a specific radio immuno-assay method. The values are represented in the diagram in the following way; the value before electric excitation with empty column, the one measured immediately after excitation with black and the one measured at 8 minutes after excitation with shaded columns. The following radio immuno-assay method was
  • Example 94 (Study of pharmaceutical effect) Examination of the in vivo neurogenic inflammation inhibiting effect.
  • BALB/c male mice of 18 to 20 g were anesthetized with ketamine (100 mg/kg according to the invention) and xylazine (10 mg/kg i. m.). Having measured the ear thickness at the base the examined substances were applied according to the invention in quantities of 0. 1 ml per 10 g. 10 minutes later Evans blue stain of 125 mg per kg (solution of 2.5 %, 0.05 ml per 10 g) was injected into tail veins then 5 minutes later 10 ⁇ l of alcohol of 96 % was applied on the left ear and 10 ⁇ l of capsaicine solution of 2.5 % was applied on the right ear of each animal. The Evans blue marker stain connects itself to the plasma albumin in the circulation.
  • the thickness of ears was measured again after 30 minutes and the swelling was defined as per cents of the initial thickness.
  • the animals were killed thereafter by bleeding to death, their ears were cut and the mass of the ears was measured.
  • the stain accumulated in the tissue pieces was extracted with 1.5 ml of formamide at 20 C° for 72 hours.
  • the optical densities of the solutions were determined by spectrophotometry (with microplate reader) at the wavelength of 620 nm.
  • the quantity of extravased stain (indicating the plasma albumin quantity) was defined in units of mg per humid tissue
  • the values measured in the ears treated in alcohol were subtracted from the ones measured in the ears treated with capsaicine at both animals.
  • the animals treated with solvent served as control.
  • the Figure 9 shows accumulation of Evans blue quantity in the control group pre- treated with solvent (black column) after administering TT-232 as reference substance and dosing of 100 ⁇ g/kg of 11 compounds according to the invention.
  • Non-parametric Mann- Whitney test was used to the statistical evaluation of the results. *p ⁇ 0.05; **p ⁇ 0.01.
  • mice Balb/c male mice were anesthetized with ketamine (100 mg/kg according to the invention) and xylazine (5 mg/kg i. m.) then albumin (30 kBq activity per mouse)
  • the partial unilateral ligation of n. ishiadicus causes diminution of the mechanonociceptive threshold of the extremity (Seltzer's operation).
  • the mechanonociception was examined with Ugo Basile's analgesimeter (Randall- Selitto test).
  • the foot of the animal was put under a teflon cone with rounded end and gradually increasing force was exerted onto middle region of the beck of foot.
  • the pain threshold is the value when the animal pulls its leg out. It may be read out in grams by the hand moving before linear scale.
  • the change of the mechanical threshold was expressed in per cents of the own initial threshold.
  • the nervus ischiadus of the thigh of male Sprague-Dawley rats was prepared on the one side in pentobarbital narcosis after control measurements then 1/3 to 1/2 part of the nerves were carefully detached, tightly bound with non-traumatic thread

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP05739554A 2004-04-29 2005-04-25 7H-PYRROLO[2,3-d]PYRIMIDINDERIVATE SOWIE DEREN THERAPEUTISCH ANNEHMBARE SALZE, PHARMAZEUTISCHE ZUBEREITUNGEN, DIE DIESE ENTHALTEN, UND VERFAHREN ZUR HERSTELLUNG DES WIRKSTOFFS Active EP1756110B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0400891A HUP0400891A2 (en) 2004-04-29 2004-04-29 7h-pyrrolo[2,3-d]pyrimidine derivatives, their pharmaceutically acceptable salts, pharmaceutical compositions containing them and process for the production of the compounds
PCT/HU2005/000040 WO2005105804A1 (en) 2004-04-29 2005-04-25 7H-PYRROLO[2,3-d]PYRIMIDINE DERIVATIVES, AS WELL AS THEIR THERAPEUTICALLY ACCEPTABLE SALTS, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND PROCESS FOR PRODUCTION THE ACTIVE AGENT

Publications (2)

Publication Number Publication Date
EP1756110A1 true EP1756110A1 (de) 2007-02-28
EP1756110B1 EP1756110B1 (de) 2010-03-31

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EP05739554A Active EP1756110B1 (de) 2004-04-29 2005-04-25 7H-PYRROLO[2,3-d]PYRIMIDINDERIVATE SOWIE DEREN THERAPEUTISCH ANNEHMBARE SALZE, PHARMAZEUTISCHE ZUBEREITUNGEN, DIE DIESE ENTHALTEN, UND VERFAHREN ZUR HERSTELLUNG DES WIRKSTOFFS

Country Status (13)

Country Link
US (1) US20080214583A1 (de)
EP (1) EP1756110B1 (de)
JP (1) JP2007534737A (de)
KR (1) KR20070047737A (de)
CN (1) CN1972946A (de)
AT (1) ATE462706T1 (de)
AU (1) AU2005238287A1 (de)
CA (1) CA2564277A1 (de)
DE (1) DE602005020281D1 (de)
HU (1) HUP0400891A2 (de)
IL (1) IL178906A0 (de)
RU (1) RU2391344C2 (de)
WO (1) WO2005105804A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013174743A1 (en) * 2012-05-21 2013-11-28 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyrimidines
WO2014145576A2 (en) 2013-03-15 2014-09-18 Northwestern University Substituted pyrrolo(2,3-d)pyrimidines for the treatment of cancer
WO2016042349A1 (en) * 2014-09-17 2016-03-24 Pécsi Tudományegyetem New agents for treating neurogenic inflammation and neuropathic hyperalgesia related disorders
RU2603770C2 (ru) * 2014-11-28 2016-11-27 Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") Замещенные пиразинопиримидиноны как блокаторы trpa1 каналов, фармацевтическая композиция, способы их получения и применения
CN110483526B (zh) * 2019-09-09 2021-10-01 辽宁大学 含芳基腙结构的吡唑并[1,5-a]嘧啶类衍生物及其应用

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Publication number Priority date Publication date Assignee Title
DE2818676A1 (de) * 1978-04-27 1979-11-08 Troponwerke Gmbh & Co Kg Substituierte 5,6-dimethylpyrrolo 2,3-d pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
CA2331468C (en) * 1998-05-19 2005-06-28 Otsuka Pharmaceutical Factory, Inc. Pyrazolo[1,5-a]pyrimidine derivatives
TR200400105T4 (tr) * 1999-12-10 2004-02-23 Prizer Products Inc. Pirrolo [2,3-d] pirimidin bileşikleri
CA2575808A1 (en) * 2004-08-02 2006-02-16 Osi Pharmaceuticals, Inc. Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005105804A1 *

Also Published As

Publication number Publication date
RU2006141393A (ru) 2008-06-10
AU2005238287A1 (en) 2005-11-10
CN1972946A (zh) 2007-05-30
JP2007534737A (ja) 2007-11-29
HUP0400891A2 (en) 2006-04-28
DE602005020281D1 (de) 2010-05-12
KR20070047737A (ko) 2007-05-07
IL178906A0 (en) 2007-03-08
ATE462706T1 (de) 2010-04-15
EP1756110B1 (de) 2010-03-31
WO2005105804A1 (en) 2005-11-10
CA2564277A1 (en) 2005-11-10
US20080214583A1 (en) 2008-09-04
HU0400891D0 (en) 2004-07-28
RU2391344C2 (ru) 2010-06-10

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